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β- Carbolines
SCHEME 1.45 Synthesis of β- carboline based chalcones.
SCHEME 1.46 Synthesis of β- carboline- 4- benzylidene- 4H- oxazol- 5- one hybrids.
free indole NH group is crucial for anticancer action. All cancer cell lines were possibly responsive to the synthesized compounds in a dose- dependent way. The fabrication of hybrids of β- carboline- 4- benzylidene- 4H- oxazol- 5- one was reported by
Savariz et al., who also assessed their anticancer effectiveness (Savariz et al. 2012).
Compound 157 was hydrolyzed by sodium carbonate under reux in methanol/ water,
and with subsequent acid hydrolysis, compound 158 was produced, which underwent
an Erlenmeyer- Plochl reaction with benzaldehyde to get the desired product,
β- carboline- 3- oxazolone motifs 159 (Scheme 1.46). Using doxorubicin as the refer-
ence medication, all prepared series of compound 159 were tested for cytotoxicity
against a panel of cancer cell lines. A SAR investigation revealed that the cytotoxic
potential of β- carboline- oxazolone hybrids was boosted by electron- donating substituent at the C1 position. The most effective molecule was discovered to have a
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β- Carbolines as Anti-Cancer Agents
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SCHEME 1.47 Synthesis of 9- substituted β- carbolines.
4- methoxyphenyl ring at the C1 position and a phenyl ring on oxazolone, with IC50
values against the U251, PC- 3, and OVCAR- O3 cancer cell lines of 0.48, 1.50, and
1.07 μM, respectively.
According to a report by Cao et al. on the synthesis of 9- substituted β- carboline
motifs 160 through the reaction of 148 with sodium hydroxide (Scheme 1.47),
harmines afnity for binding to DNA could be increased by adding a suitable substituent to its N- 9 position, which in turn increases Topo I inhibition.When electronreleasing substituents were applied, such compounds started to exhibit improved
cleavage efciency. For instance, a molecule with an n- butyl substituent at the N- 9
position demonstrated the strongest anticancer action, with an IC50 value of 11.0 μM
against Lovo.
Alkyl linked bivalent β- carboline motifs were synthesized, and their biological
evaluation was published by Chen et al. Compound 161 produces the Schiff’s base
when combined with the appropriate sym- diamines, and when this base is reduced
with NaBH3CN, the required compound 162 is produced (Scheme 1.48). Using
Endostar as the standard reference, the capacity to suppress these drugs was assessed
against the human umbilical vein cancer cell line EAHY26. The ndings revealed
striking antiproliferative actions, and some drugs displayed IC50 values between 2.16
and 5.0 μM. The vascular targets of anticancer medication are affected by these bivalent β- carboline motifs (Chen et al. 2016).
Gu et al. also described the synthesis of a number of bivalent β- carboxyline motifs
that were tested against a variety of cancer cell lines, including BGC- 823, A- 375,
P- 769, and SK- OV- 3. In order to create symmetrical bivalent β- carboline motifs
164, a monovalent β- carboline- 3- carboxylic acid 163 was combined with the appropriate dibromoalkane in anhydrous DMF (Gu et al. 2018) (Scheme 1.49). Compound
164 with the highest potential was found to exhibit a 64.2% inhibition rate against
Lewis lung carcinoma in mice. At a dose of 26.9 mmol/ kg, a compound with a
3- phenylpropyl group at the C- 9 position of the β- carboline ring inhibited Lewis lung
cancer in mice with a rate of 53.5%.
The preparation of simple dimeric β- carboline motifs and assessment of their cytotoxic potential against various cancer cell lines were both attested by Chatwichien
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β- Carbolines
SCHEME 1.48 Synthesis of alkyl linked bivalent β- carbolines.
et al. Condensation of 1- formyl- β- carboline 165 with linkers was used to create dimers
of β- carboline motifs, which were then reduced with sodium cyanoborohydride to
produce 166 and 167 (Scheme 1.50). According to studies, dimers are more effective
than monomers against the cancer cell lines H1299 and A375, with IC50 values of 1.6
and 2.0 μM, respectively (Chatwichien et al. 2015).
Sun et al. described the preparation of piperazine- linked β- carboline, which has
superior antitumor activity and an improved solubility prole (Sun et al. 2015). In the
synthesis, compound 163 and piperazine were stirred in the presence of anhydrous
dichloromethane at 60 °C, and the desired compound 168 was then produced by further reducing anhydrous dichloromethane with NaBH3 at room temperature (Scheme
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β- Carbolines as Anti-Cancer Agents
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SCHEME 1.49 Synthesis of bivalent β- carbolines.
1.51). Utilizing cisplatin as the standard reference, the anticancer activity of each
of the synthesized bivalent β- carboline motifs 168 was assessed against a variety of
cancer cell lines. The C1 and C9 positions of β- carbolines were signicantly more
important in the SAR study’s demonstration of their contribution to anticancer action.
The cytotoxic potential of β- carboline motifs was improved by adding an alkyl group
at the C9 position; the tert- butyl substituent was thought to be the best. With IC50
values of 7.62, 8.95, 5.32, 3.02, 8.35, 5.51, 7.62, and 5.5 μM against MCF- 7, HepG2,
22RV1, 769- P, A- 375, SK- OV- 3, BCG- 823, and LLC cancer cell lines, respectively,
the most potent cytotoxic molecule was examined.
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β- Carbolines
SCHEME 1.50 Synthesis of dimeric β- carbolines.
SCHEME 1.51 Synthesis of piperazine- linked bivalent β- carbolines.
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β- Carbolines as Anti-Cancer Agents
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SCHEME 1.52 Synthesis of 1,2,3- trazole- tethered β- carbolines hybrids.
Salehi et al. described a methodical approach to the systematic preparation of H- 1,
2, 3- triazole- tethered- β- carboline hybrids and assessed their potential for anticancer
action (Salehi et al. 2016). The intended 1H- 1,2,3- trizoletethered β- carboline hybrid
171 was produced by treating the o- propargylated β- carbolines 169 with a number
of alkyl/ aryl azides 170 by a Cu- promoted azidealkyne cycloaddition reaction
(Scheme 1.52).
Using paclitaxel as a positive control, all the prepared compounds were tested
against cancer cell lines. The most effective molecule out of these 171 was discovered
to contain a fragment of 3,4- dichlorophenyl as azide, which had an IC50 value of 46
and 32 μM against the HeLa and HepG2 cancer cell lines, respectively.
Drug resistance is brought on by the efux of medicines from cancer cells by the
breast cell resistance protein (ABCG2/ BRCP1). Spindler et al. developed ABCG2/
BRCP1 as a result to prevent this outow (Spindler et al. 2016). Using the Pictet–
Spengler method, tryptamine or 5- hydroxytryptamine 172 reacts with various
aldehydes 173 in the presence of dichloromethane and TFA to yield 1- substituted
tertahydro- β- carbolines or 1,6- disubstituted tetrahydro- β- carbolines 174. These sub-
sequently react with substituted benzoyl chloride 175 using THF and TEA, yielding
Tetrahydro- β- carbolines replaced with N- 2- acyl- 1 or N- 2- acyl- 1,6- disubstituted with
N- 2- acyl- 1 176 (Scheme 1.53).
Similar to Ko143 in terms of inhibitory activity, two compounds prefer BRCP1/
ABCG2 over ABCB1 over ABCB1. The drugs also reversed SN- 38 resistance
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SCHEME 1.53 Synthesis of N- 2- acyl- 1,6- disubstituted tetrahydro- β- carbolines.
β- Carbolines
mediated by BRCP1/ ABCG2, but the effect of Ko143 was less effective. The sample
showed separate membranes with basal ATPase activity from Spodoptera frugiperda
ovarian cells (Sf9) infected with a recombinant baculovirus expressing ABCG2/
BRCP1.
1. 4 CONCLUSIONS AND FUTURE PERSPECTIVES
Cancer has emerged as one of the leading causes mortalities worldwide. Various
treatment modalities, such as chemotherapy, radiation therapy, and sometimes surgery, are employed to control the disease, depending on its type and severity. Despite
a great deal of unneeded investigation that has been performed in the medical eld,
there are still numerous areas wherein researchers can make improvements to address
this troubling clinical issue. For cancer treatments, combination therapy has become
popular since it prevents resistance from growing and outperforms single agents in
terms of effectiveness. Eliminating cancer progenitor cells should be the next step
in the ght against cancer because they often exhibit drug resistance and have the
potential to induce remission. Research needs to be done in this area in order to
comprehend the basic mechanisms underlying cancer medication resistance and to
identify drugs that can treat tumors without running the risk of developing resistance.
In the interim, several novel approaches can be further investigated using currently
available drugs. There are now a number of studies being published on the usage of
β- carboline derivatives as possible cancer therapies. This chapter outlined the biological evaluation and synthesis of many β- carboline- based compounds, grouping
them depending on the expected activities. According to observations collected, the
approach employed in the referenced publications to analyze the anticancer effects
against different cancer cell lines primarily involved molecular docking analysis. The
interactions between anticancer motifs and cancer cells were also examined using
contemporary techniques including UV- Vis study. There is potential for more research
on cancer treatments using cutting- edge spectroscopic investigations to comprehend
how the drugs function on target cells.
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β- Carbolines as Anti-Cancer Agents
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